An editorial about personalized medicine should perhaps start with a definition. Although
several versions of such definition exist, we pay homage here to the oldest definition
reported in modern medical literature. Sir William Osler (1849-1919) recognized that
"variability is the law of life, and as no two faces are the same, so no two bodies
are alike, and no two individuals react alike and behave alike under the abnormal
conditions we know as disease". Modern day medicine recognized this fact and implemented
its ethos since inception of its practice separating it from a general "one-size-fits-all"
approach. A medical doctor would ask the patient about his/her suffering and prescribe
a treatment suited to the patient's condition. Individualized evaluation and treatments,
which include history taking, focused examination and specific laboratory and medical
tests have now become routine in day-to-day medical practice. Personalized medicine,
takes into account the needs of individual patients, and provides custom-tailored
therapeutic approaches.
More recently, modifying life style approaches as part of a broad preventive medicine
orientation, are gaining popularity and yielding positive results. Weight management,
smoking cessation and healthy diet are well-established preventive strategies that
have a contributed a great deal in reducing mortality associated with chronic diseases.
But there are challenges. For example, losing weight is easy. But, maintaining it
at an optimum level is a challenge!
Similarly, limits of existing diagnostic and therapeutic strategies are becoming well-known.
Despite all the impressive advances in imaging technology, advent of new medical diagnostics,
and burgeoning of therapeutic interventions, the widespread prevalence of disability
and premature mortality associated with chronic conditions such as diabetes, cancer
and heart disease continues to frustrate scientists and clinicians alike. There are
also many unanswered questions. Here is one such question. Why two patients with exactly
the same diagnosis and identical test results respond differently to the same treatment.
Have we reached a glass ceiling? Are we limited in our scientific understanding of
disease and health? Rapid advances in genotyping and genomics might shed some light.
Let us look at example of the oral anticoagulant drug Warfarin that is used for the
long-term management of thromboembolic events. Studies have shown that of over 21
million patients, who are on Warfarin in the USA, some suffer from its adverse effects
[1] and others don't. Why? Research has shown that there is a variant nucleotide in
the Cytochrome P450 CYP2C9, which is responsible for this variation observed in the
drug response [2]. Other genetic variations that alter the personal response to Warfarin
also exist in the Vitamin K epoxide reductase complex protein 1 (VKORC1) [3]. The
U.S. Food and Drug Administration (FDA) has recognized and acknowledged the importance
of genotyping CYP2C9 and VKORC1 during Warfarin treatment [4,5]. In doing so, it has
given the field of genomics a tremendous boost.
Let us take a look at another example. Trastuzumab is a very effective drug for breast
cancer treatment. However, only 10-20% of the breast cancer patients can benefit from
it. This is due to the fact that Trastuzumab is based on monoclonal antibodies targeting
the Epidermal Growth Factor Receptor (HER2/neu/EGFR) [6]. Therefore only patients
with amplification (multiple copies) of HER2/neu/EGFR will respond to this treatment.
The availability of Trastuzumab has created a research drive at a frantic pace, to
standardize the detection of HER2/neu/EGFR amplification, for which several methods
are now available.
The utility of genomics in personalized medicine is gaining popularity. Its potential
for predicting disease occurrence is receiving worldwide attention and illustrated
by examining the relationship between certain allele's and cancer risk. For example,
the presence of mutant BRCA1 or BRCA2 allele substantially increases the risk of breast
and/or ovarian cancer. Similarly, the presence of certain variant single nucleotide
polymorphisms (SNPs, e.g. FGFR2) also significantly escalates the probability of developing
breast cancer. Specific SNPs have also been identified which are associated with increased
risk of diabetes, rheumatoid arthritis or chronic heart disease as well as other multi-factorial
diseases. This list is continuously being updated as additional SNPs are being identified
from a wide range of promising genome-wide association studies, which are underway
throughout the world. Technology aimed at predicting disease and health outcomes is
gaining momentum.
The promise of genomic evaluation as an integral component of personalized medicine
is fast becoming a reality in many nations around the world. The recent announcement
of the formation of the Genomic Cancer Care Alliance between one of the biggest providers
of next-generation sequencing solutions, Life Technologies, and leading research centers
such as Fox Chase Cancer Center, Scripps Genomic Medicine, and the Translational Genomics
Research Institute (TGen) is an illustration of that reality. The goal of this alliance
is to launch a pilot study aimed at determining whether whole-genome sequencing can
positively affect the treatment decisions across a number of cancers with limited
treatment options. Research laboratories with access to the high-throughput sequencing
technology are already implementing Whole-Exome Seq in the identification of genetic
causes of congenital abnormalities, such as congenital hearing loss.
Current concept of 'Personalized medicine' approach thus incorporates the traditional
assessment methods, genotyping, and genomic evaluation in predicting disease risk
and treatment outcomes. Additionally, it encourages patients to participate in their
own care: participative component of personalized medicine. Research has shown that
patients who participate in their own care have better outcomes than patients who
don't [7].
Most health care 'gurus' agree that health care will become more person-specific in
its approach, and will be driven by the patients' felt needs, their perceptions about
health and disease and their behavior. Taking into account the patient's behavior
and other factors surrounding the doctor-patient relationship in managing disease
and illness is vital, and will become more important in years ahead.
It is well known that human factors, which significantly improve disease outcomes,
are many [8]. Healing words, pleasant environment, and family and social support,
to name a few, are well known examples of such factors. Patient feelings and attitudes
also matter. Positive attitude and feelings result in better outcomes. Negative feelings
and hopelessness, on the other hand, can have detrimental effects. There is now evidence,
for example, that hopelessness accelerates carotid atherosclerosis [9].
Interaction between the doctor and the patient is vital in the overall healing response.
Empathy, caring and helping patients cope with their suffering have a real impact
on patient outcomes.
There are many scientists who concur that many human factors, placebo or context factors
as some may call them [8], described above may be operating via psychoneuroimmunology
paradigm [10], which is "the complex interrelationship between the mind or psychology,
the brain, the immune system and general health". A recent study showed an association
between genetically controlled amygdala activity and placebo-induced relief from anxiety.
This is a striking observation and will no doubt lead to additional research initiatives
on this subject [11] Soon, we will see scientists beginning to identify allele's and
SNP which guide human behavior and factors (placebo and context effects). That information
could be immensely helpful in optimizing healing responses in certain individuals.
The genomics technology is advancing at a rapid pace. The cost of sequencing whole
human genomes is now within reach of most research laboratories. As the technology
continues to grow and advance we need to be mindful of the challenges and questions
that the upcoming discipline of 'personalized medicine' is likely to present in times
ahead. The key question for a health care provider is who will pay the high for the
use of personalized genomics? In the U.S.A, medical insurance companies are so far
resisting re-imbursements for routine genetic testing delaying the implementation
of personalized medicine. It remains to be seen how such technology will be paid for
in other countries like the United Kingdom where the health service is largely funded
by the public sector (National Health Service, NHS).
Here is another challenging question. How likely is it that individual genome information
may be used to discriminate against people with negative health and personal traits?
This could be a serious ethical issue that the law and policy makers may have to grapple
with in times ahead. Protecting the confidentiality of the genomic information will
also be of concern.
Despite some of the concerns noted above, personalized medicine is the way forward.
It is a melding of traditional (e.g., personalized history, examination, and laboratory
tests) and novel approaches, e.g., genotyping, genomic evaluations). It uses the science
of prediction, principles of modern therapeutics and prevention, and optimizes active
participation of patients in their own care. Treating the patient as a person (with
his/her human attributes) and not just their illness is also an essential element
of this approach. This wholesome and person-centered approach to health care should
improve outcomes, reduce morbidity and mortality, and at the same time alleviate pain
and human suffering commonly associated with chronic illnesses such as cancer and
heart disease.